HHV-8/KSHV, one of the sexually transmitted agents in U.S.A. is associated with a variety of human diseases and neoplasm. Our long term objective is to define the early events of HHV-8 infection of target cells with a rationale that this is vital for a through understanding of HHV-8 pathogenesis which will lead into novel methods to control HHV-8 infection. The interactions of eukaryotic cells with their extracellular environments are largely mediated by ligand-induced signaling molecules exposed at the cell surface. The ensuing multitudes of biological processes are mediated by highly interlinked networks of signaling pathways. Ligand mimicry is an opportunistic mechanism by which microbes subvert host signaling molecules for their entry into the host cells. There is a dearth of knowledge regarding the mechanism by which herpesvirus-receptor interactions facilitate infection. Binding of herpesviruses to the cell surface can occur at 4[unreadable]C in an energy independent manner. In contrast, entries into cells and the subsequent transfer of capsids to the vicinity of the nucleus are active, energy dependent phenomenon, and thus must be requiring host-cell signaling pathways. HHV-8 uses its envelope gB and gPK8.1 A to make the initial contact with the target cell surface heparan sulfate (HS) molecules, which is probably the first set of ligand-receptor interaction leading to the binding with other host cell receptors essential for the subsequent viral entry process. We have demonstrated that HHV-8 utilizes the ?3?1 integrin as one of its entry receptor. Ongoing studies show that HHV-8 also utilizes the ?v?3 and ?v?5 integrins as entry receptors. Our studies show that HHV-8 utilizes the endocytic pathway for its entry in the human foreskin fibroblast (HFF) cells. Our studies also show that HHV-8 induces the phosphorylation of integrin-dependent focal adhesion kinase (FAK). We hypothesize that besides a conduit for the entry of viral genome into the interior of the cells, interaction of HHV-8 with integrins must have an active role in the induction of host-cell pre-existing signaling cascades for the rapid internalization of viral genome and for transport to the nucleus. The specific aims of this grant are to analyze in detail the various mode of HHV-8 entry into the different target cells, subsequent movement in the cytoplasm, and delivery of viral DNA to the nuclei of infected cells, and to determine the role of HHV-8-induced signal mediators in these early events. These studies are significant, since they would provide an insight into the early events of HHV-8 infection of target cells. Further understanding of HHV-8-entry, integrin-dependent cell signaling pathways, and their role in infection would eventually lead to the development of new anti-HHV-8 agents.